Embodiments described herein relate in general to a fluid delivery device that includes an electrochemical pump for controllably delivering small volumes of fluid with high precision and accuracy. The fluid delivery rate of the device can also be changed during operation.
In many medical situations, it may be necessary or at least desirable to deliver small amounts of fluids and/or chemical agents over a relatively long period of time. Such fluids may include biologicals, drugs, lubricants, fragrant fluids, and chemical agents. A common example of such an application is the gradual administration of a pharmaceutical agent into the living (e.g., human) body. A very common and traditional apparatus for the gradual administration of fluid into the human body is an intravenous administration set in which gravity induced hydrostatic infusion dispenses a fluid from a familiarly suspended bottle or bag above the patient.
Other methods for the gradual administration of fluids have been devised to eliminate the need for suspending the fluid above the patient and thereby provide the patient with greater mobility. One such method utilizes a diffusion controlled delivery pump wherein the fluid diffuses through a membrane at a constant rate. The rate of delivery may be adjusted by varying the nature of the membrane and the concentration of the solution in contact with the membrane, e.g., a transdermal drug delivery patch. Additional transdermal technologies include: iontophoresis, in which low voltage electrical current is utilized to drive charged drugs through the skin; electroporation, in which short electrical pulses of high voltage is utilized to create transient aqueous pores in the skin; sonophoresis, in which low frequency ultrasonic energy is utilized to disrupt the stratum corneum; and thermal energy, in which heat is utilized to make the skin more permeable and to increase the energy of drug molecules. Even magnetic energy, or magnetophoresis, has been investigated as a way to increase drug flux across the skin. Of these transdermal technologies, only iontophoresis has been successfully developed into a marketable product, albeit for local pain relief. A transdermal system may not be the preferred method for gradually administering fluids in every case, and various factors should be considered that may affect its usefulness, such as: the adhesive utilized to secure the system to the individual may not adhere well to all types of skin; some drug formulations may cause skin irritation or allergy; the transdermal system may be uncomfortable to wear or too costly; and some drugs that require high blood levels (low potency) cannot be properly administered.
A mechanical pump dispenser is yet another mechanism for gradually administering fluids to an individual. The conventional mechanical pump dispenser utilizes various types of mechanical pumps to expel the fluid from a reservoir. Some processes incorporating a mechanical pump dispenser include: a continuous intravenous infusion pump system, for example from Intevac Inc.; an epidural infusion system; and a subcutaneous infusion system, e.g., utilizing a portable insulin infusion pump. An externally worn pump is also conventionally used with a transcutaneous catheter; however, the external pump is often bulky and inconvenient because it is typically strapped onto the wearer, or carried on a belt or in a harness. A common drawback of the mechanical pump is that the required entry site into the body is susceptible to infection. In addition, most mechanical pumps are designed to deliver relatively large quantities of fluid and do not effectively dispense small volumes over longer time periods.
Other fluid delivery processes utilize pressure to administer a fluid to the individual. For instance, a charged reservoir dispenser stores a fluid under pressure in a flexible reservoir and then selectively expels the fluid by the force of internal reservoir pressure—the rate of release is often regulated by a plurality of complex valve systems. The pressurized gas dispenser implements a pressurized gas to expel the fluid, while an osmotic dispenser relies on a solute that exhibits an osmotic pressure gradient against water to dispense the fluid. The OROS® system produced by ALZA Corporation is an example of an osmotically driven system in which osmosis is the energy source for drug delivery. In the OROS® system, the drug solution flows from a tablet at a constant zero-order rate as the tablet progresses through the gastro-intestinal (GI) tract until the entire solid drug in the core is dissolved or until the unit is eliminated. In vivo and in vitro testing has shown that the delivery rate is independent of GI motility, pH, and food in the gastro-intestinal tract. The release of the drug is controlled by the solubility of the drug in gastric fluid, the osmotic pressure of the core formulation, and the dimensions and permeability of the membrane.
In addition to the above-identified fluid administration device types or techniques, there are a number of conventional implantable drug delivery pumps and systems. One widely used implant is the large capacity (18 mL) programmable electromechanical SynchroMed® pump. While applicable in a number of therapies, several drawbacks of the SynchroMed® pump are its cost, the overall cost of the therapy, and that surgery is required for placement of the large pump.
Smaller sized implantable drug delivery pumps are also available such as the osmotic pump of the DUROS® system. Generally, the osmotic pump involves imbibing water or another driving fluid. The pump includes three chambers: a salt chamber, a water chamber, and a fluid chamber. The salt and water chambers are separated by a semi-permeable membrane. This configuration creates a high osmotic driving force, e.g., environmental osmosis, for water transport across the membrane. This membrane is permeable to water, but impermeable to salt. The fluid chamber is separated from the other two chambers by a flexible diaphragm. Water imbibes osmotically into the salt chamber creating substantial hydrostatic pressures, which in turn exert a force on the displaceable member, e.g., diaphragm—thus expelling the fluid. The use of osmotic pumps is typically directed to applications for constant fluid delivery. In order to vary the fluid flow, it is often necessary to provide numerous osmotic pumps with differing outputs. The osmotic pump also requires charging—the time required for liquid to diffuse through the semi-permeable membrane and begin dissolving the osmagent at steady state—which in turn delays delivery of the active and further limits its suitability for instantaneous or emergency use. The fluid delivery rate of the osmotically driven device typically cannot be changed or turned off. In other words, it possible to shut off the delivery of the fluid after commencement of delivery.
With further reference to some specific types of conventional osmotic pumps, water is imbibed osmotically through a membrane into a salt chamber pressurizing a piston to expand into a drug chamber to force a drug out through a delivery orifice. The driving force behind the drug delivery of this pump is osmotic pressure, which can be as high as 200 atmospheres depending on the salt used, even though the pressure required to disperse the drug from the device is small and the drug delivery rate remains constant as long as some excess undissolved salt remains in the salt chamber. In comparison with mechanically driven devices, osmotic systems are small, simple, reliable, and less expensive to manufacture. Because of the small size of the osmotic system, it can be implanted during a simple procedure in the physician's office. On the other hand, the fixed delivery rate of the conventional osmotic pump in not adjustable during its operation.
In addition to osmotic pumps, some forms of electro-osmotic pumps are used. An electro-osmotic pump is an electrolytic cell having a permselective ion exchange membrane and therefore requires an external DC power source to drive the electrode reactions. In some conventional embodiments, an electrochemically driven fluid dispenser based on electro-osmotic fluid transport. The pump includes a plastic housing having a fluid inlet and outlet, a pair of spaced silver-silver chloride electrodes disposed in the housing and connected to a DC power source, a porous ceramic plug that has a high zeta potential relative to the fluid, a cation exchange membrane positioned on each side of the ceramic plug between it and the electrode facing it, and a passageway in the housing extending from the fluid inlet to one side of the plug and from the other side of the plug to the outlet. When a potential difference is applied across the anode and cathode, the transport fluid will flow through the porous plug from the anode to the cathode. One particular disadvantage of this electro-osmotic pump with a porous plug is that the delivery pressures are very low, well below 0.5 ATM. In addition, any ions in the driving fluid will substantially affect the zeta potential and reduce the electro-osmotic flow. Another disadvantage of this electro-osmotic pump is that it requires an external DC power source that lessens the overall volume efficiency of the fluid delivery device.
Gas generating devices that are both portable and accurate for dispensing small volumes are also used in drug delivery systems. These gas-generating methods include galvanic cells and electrolytic cells. By definition, a galvanic cell is an electrochemical cell that requires no externally applied voltage to drive the electrochemical reactions. In galvanic gas generating cells, hydrogen or oxygen gas is formed at the cathode or anode, respectively, as a result of a reaction between a metal or metal oxide and an aqueous electrolyte. Typically, the anode and cathode of the galvanic cell are connected through a resistor that regulates the current passed through the cell, and in turn, directly regulates the production of gas that exerts a force on a diaphragm or piston—thereby expelling the drug.
Other conventional delivery systems are based on the use of galvanic hydrogen generating cell. In these types of cells, a zinc anode reacts with an alkaline electrolyte producing zinc oxide and water molecules are reduced on a porous carbon electrode producing gaseous hydrogen. In other conventional cells, a galvanic oxygen-generating cell that is constructed much like a zinc/air button cell, in which a reducible oxide is reduced at the cathode while hydroxyl ions are formed. The hydroxyl ions oxidize at the anode and release oxygen.
In contrast to the galvanic cell, an electrolytic cell uses an external DC power source to drive the electrochemical reactions. When voltage is applied to the electrodes, the electrolyte gives off a gas that exerts a force on a diaphragm or piston, thus expelling the fluid. At least three types of electrolytic gas generating cells have been proposed for use in fluid delivery devices. A first type is based on water electrolysis requiring an operating voltage over 1.23 V. A second type, also known as oxygen and hydrogen gas pumps, uses a lower DC voltage than that utilized in water electrolysis systems. Both of these cell types utilize an ion exchange polymer membrane. A third type of gas generating electrolytic cell is based on the use of an electrolytically decomposable chemical compound that produces a reduced metal at the cathode, and generates gaseous oxygen by oxidation of water at the anode.
Another type of device is an electrochemically driven fluid dispenser based on the electrolysis of water. In this dispenser, water is contained in an electrochemical cell in which porous metal electrodes are joined to both sides of a solid polymer cation exchange membrane, and both of the two electrodes are made to contact with the water so as to use oxygen or hydrogen generated from an anode or cathode respectively, upon current conduction. Thus, hydrogen, oxygen, or a gas mixture of hydrogen and oxygen—generated by electrolysis of water when a DC current is made to flow between the electrodes—is used as a pressurization source of the fluid dispenser.
Electrochemical oxygen and hydrogen pumps are constructed in a similar manner to the above-discussed water electrolysis cell. Conventional electrochemically driven fluid dispensers have an electrochemical cell in which porous gas diffusion electrodes are joined respectively to the opposite surfaces of an ion exchange membrane containing water functioning as an electrolyte. The electrochemically driven fluid dispenser uses such a phenomenon that when hydrogen is supplied to an anode of the electrochemical cell and a DC current is made to flow between the anode and the cathode, the hydrogen becomes hydrogen ions at the anode. When the produced hydrogen ions reach the cathode through the ion exchange membrane, an electrochemical reaction arises to generate gaseous hydrogen. Since the net effect of these processes is the transport of hydrogen from one side of the membrane to the other, this cell is also called a hydrogen pump. The hydrogen generated and pressurized at the cathode is used as a driving source for pushing a displaceable member, e.g., a piston, a diaphragm, or the like. Alternatively, oxygen may be used in place of hydrogen as a reactant in this type of electrochemical cell, so that the cell then acts as an oxygen pump. Thus, oxygen is reduced on one side of a water-containing electrolytic cell and water is oxidized on the opposite side to generate molecular oxygen, wherein the molecular oxygen so generated is used as the propellant to force liquid from an adjacent reservoir.
A gas generating electrolytic cell using an electrolytically decomposable chemical compound that produces a reduced metal at the cathode and generates gaseous oxygen by water oxidation at the anode is also known. This type of cell generally includes a graphite anode, an aqueous electrolyte, and a copper hydroxide cathode. As electrical current passes through a circuit in which the cell is connected, copper is plated out in the cathode and oxygen is released at the anode. To ensure storage stability, an active cathode material is selected such that the cells use an applied voltage for the electrochemical reactions to proceed. A battery cell is provided in the circuit to drive the current through the gas-generating cell. The rate of oxygen generated at the anode is directly proportional to the current and acts as a pressurizing agent to perform the work of expelling a fluid from a bladder or other fluid-containing reservoir, which has a movable wall that is acted upon as the gas is generated.
While the above-identified electrochemically driven fluid delivery devices are operable for certain applications, they are not optimal for others. In particular, gas generating cell based pumps are sensitive to temperature and atmospheric pressure. For this reason, osmotic and electro-osmotic pumps are often more appropriate.